PXD053582

PXD053582 is an original dataset announced via ProteomeXchange.

Title	Protein misfolding involving entanglements provides a structural explanation for the origin of stretched-exponential refolding kinetics
Description	Stretched-exponential protein refolding kinetics, first observed decades ago, were attributed to a nonnative ensemble of structures with parallel, non-interconverting folding pathways. However, the structural origin of the large energy barriers preventing interconversion between these folding pathways is unknown. Here, we combine simulations with limited proteolysis (LiP) and cross-linking (XL) mass spectrometry (MS) to study the protein phosphoglycerate kinase (PGK). Simulations recapitulate its stretched-exponential folding kinetics and reveal that misfolded states involving changes of entanglement underlie this behavior: either formation of a nonnative, noncovalent lasso entanglement or failure to form a native entanglement. These misfolded states act as kinetic traps, requiring extensive unfolding to escape, which results in a distribution of free energy barriers and pathway partitioning. Using LiP-MS and XL-MS, we propose heterogeneous structural ensembles consistent with these data that represent the potential long-lived misfolded states PGK populates. This structural and energetic heterogeneity creates a hierarchy of refolding timescales, explaining stretched-exponential kinetics.
HostingRepository	PRIDE
AnnounceDate	2025-03-18
AnnouncementXML	Submission_2025-03-17_18:33:22.130.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yingzi Xia
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	carbamoylated residue; acetylated residue; monohydroxylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-02 17:23:27	ID requested
⏵ 1	2025-03-17 18:33:22	announced

Jiang Y, Xia Y, Sitarik I, Sharma P, Song H, Fried SD, O'Brien EP, Protein misfolding involving entanglements providesa structural explanation for the origin of stretched-exponential refolding kinetics. Sci Adv, 11(11):eads7379(2025) [pubmed]

10.1126/sciadv.ads7379;

submitter keyword: folding, crosslinking mass spectrometry, stretched-exponential kinetics

Stephen Fried
contact affiliation	Assistant Professor, Department of Chemistry Assistant Professor, Thomas C. Jenkins Department of Biophysics (by courtesy)
contact email	sdfried@jhu.edu
lab head
Yingzi Xia
contact affiliation	Johns Hopkins University
contact email	yxia39@jhu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053582
     1. Label: PRIDE project
     2. Name: Protein misfolding involving entanglements provides a structural explanation for the origin of stretched-exponential refolding kinetics